Compounds of formula II:
and pharmaceutically acceptable salts thereof, useful as selective β3 receptor agonists, were disclosed by Heath, et al., in European Patent Publication No. 817,627 (Heath).
Example 126 from Heath disclosed the synthesis of a hemi-succinate salt of a formula II compound having the structure:
hereafter referred to as “SAM Classic”.
Said synthetic procedures described the production of an “amorphous form” of SAM Classic “containing only trace residual ethanol”. Heath described the production of the amorphous SAM Classic by solvent exchange of the ethanol in the crystalline ethanolic solvate of SAM Classic with water. In particular, Heath taught that “The mixture (from the water slurry) was vacuum filtered, and the filter cake was washed with water (3×100 ml). The solid was air dried under vacuum for approximately 2 hours then in a vacuum oven (65° C.) overnight. This gave (amorphous) product as an off white solid.” Thus, Heath discloses that in the process of drying the wet cake material, the crystal structure of the initially isolated material (present as a wet cake) collapsed to form the amorphous SAM Classic.
Poorly crystalline materials, in particular amorphous materials, are typically less desirable than highly crystalline materials for formulation processing. In addition, it is generally not desirable to formulate pharmaceuticals containing substantial amounts of organic solvent due to potential solvent toxicity to the recipient thereof and changes in potency of the pharmaceutical as a function of the solvent. Although the amorphous SAM Classic prepared by the procedures taught in '474 could be used as a pharmaceutical, it would be highly desired and advantageous to find a stable crystalline form of SAM Classic that did not contain substantial amounts of organic solvent within its crystal structure which could be reproducibly and efficiently prepared on a commercial scale.
Surprisingly, and in accordance with the invention, it has now been discovered that a crystalline hydrate of SAM Classic is capable of reproducible production, isolation and formulation on a commercial scale, is sufficiently stable for use in oral formulations, and can be produced and isolated in a highly crystalline state.